Metabolism and mechanisms of action of 9-(tetrahydro-2-furyl)-6-mercaptopurine in Chinese hamster ovary cells.
The mechanisms of action of 9-(tetrahydro-2-furyl)-6-mercaptopurine (THFMP) have been studied in Chinese hamster ovary (CHO) cells in tissue culture. THFMP is relatively unstable in physiological buffers, being facilely converted to 6-mercaptopurine (6-MP) even in the absence of cells. Consequently, THFMP undergoes metabolic conversions characteristic of 6-MP, namely formation of 6-thioIMP and incorporation into DNA as 6-thio-guanine (6-TG) nucleotide. A number of purines are capable of preventing the toxicity of THFMP in wild-type cells in a manner similar to that of 6-MP. However, exogenous purines and pyrimidines did not prevent the toxicity of THFMP to cells deficient in the enzyme, hypoxanthine-guanine phosphoribosyltransferase (EF 2.4.2.8; HGPRTase). Cells lacking HGPRTase were 20--40-fold resistant to 6-TC and 6-MP but were only 2--4-fold resistant to THFMP. Furthermore, the time-course for killing CHO cells deficient in HGPRTase was different from that in wild-type cells containing the enzyme. There was no apparent effect of THFMP on the utilization of precursors for DNA, RNA or protein synthesis in the enzyme-deficient mutant cell line. The results suggest that THFMP is converted non-enzymatically to 6-MP and shares its mechanisms of action in wild-type cells containing HGPRTase, i.e., inhibition of de novo purine biosynthesis and incorporation into DNA as 6-TC nucleotide. However, the mechanism of action of THFMP in cells lacking HGPRTase is probably unique and is presently unknown.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D010430:Pentosyltransferases / Q000378:metabolism; D013997:Time Factors
C020397:6-mercapto-9-(tetrahydro-2-furyl)purine; D015122:Mercaptopurine; D010430:Pentosyltransferases; D007041:Hypoxanthine Phosphoribosyltransferase